Increasingly recognized symbiosis between enteric commensal microbes and the mammalian host promotes systemic immune cell activation, along with intestinal tissue homeostasis. Conversely, disruptions in the composition of intestinal commensal bacteria are consistently linked with intestinal and systemic inflammatory disorders, along with susceptibility to infection in extra-intestinal tissues. These immune modulatory properties are driven by recognition of commensal bacterial products through host receptors that also initiate innate host defense against pathogenic infection. Thus, tonic stimulation by intestinal commensal microbes confers potent systemic immune modulatory properties that can be exploited for therapeutically fine- tuning activation of immune responses. Nonetheless, given the near exclusive focus on intestinal bacteria in characterizing the immune modulatory properties of commensal microbes, the symbiotic relationship between non-bacterial commensal microbes (e.g. fungi, viruses) and mammalian host remain poorly defined. To address these critical gaps in knowledge, we developed an innovative model to investigate the immune modulatory properties of enteric commensal fungi by recolonizing mice depleted of intestinal bacteria with Candida albicans. Following antibiotic induced eradication of enteric commensal bacteria, oral Candida albicans inoculation results in prolonged high-density re-colonization throughout the intestinal tract. Our initial studies show Candida albicans colonization eliminates susceptibility to intestinal injury and inflammation that occurs after depletion of intestinal commensal bacteria. These results parallel recent findings demonstrating mono-colonization with enteric norovirus can replace commensal bacteria in protection against aberrant intestinal inflammation, and together indicate tonic stimulation by intestinal fungi or viruses can each efficiently bypass the need for enteric commensal bacteria in maintaining intestinal homeostasis. At the same time, these findings also expose exciting new questions with regards to how non-bacterial commensal microbes calibrate responsiveness of systemic immune cells, evade activation of antigen-specific immune cells that prevents intestinal inflammation, and host cell receptors that sense commensal fungi in promoting intestinal and systemic immunological shifts. Exploratory studies that uniquely combine cutting edge immunological, transgenic mouse, and recombinant microbial tools designed to shed light on these fundamental questions regarding the symbiotic relationship between commensal enteric fungi and mammalian host will be addressed in the following specific aims: establish shifts in systemic immune cell responsiveness controlled by commensal enteric fungi (Aim 1); identify differentiation and activation properties for commensal Candida albicans specific T cells (Aim 2); and determine whether immune modulation by commensal fungi requires host sensing through the beta-glucan pattern-recognition receptor, dectin-1 (Aim 3).